The present invention relates to PDGF receptor kinase inhibitory compounds and compositions such as, but not limited to, slow release compositions. More particularly, the present invention relates to novel compounds and compositions of the quinoxaline family which are potent PDGF receptor kinase inhibitors, their synthesis, and their use for treatment of proliferative malignant and non-malignant diseases or disorders, such as, but not limited to, atherosclerosis, restenosis, vascular graft restinosis, instent stenosis, pulmonary fibrosis, glomerular nephritis, rheumatoid arthritis and PDGF receptor associated malignancies, such as, but not limited to, leukemias and limphomas.
Platelet derived growth factor (PDGF) is a potent mitogen for mesenchymal, glial, and capillary endothelial cells (for reviews, see, 1! and 2!). The three isoforms of PDGF, PDGF-AA, PDGF-AB, and PDGF-BB, interact differentially with structurally related receptors designated PDGF .alpha.- and .beta.-receptors. Each of these receptors has an extracellular part featuring five immunoglobulin-like domains and an intracellular part with a tyrosine kinase domain containing a characteristic insert amino acid sequence 3-5!. The tyrosine kinase activity of these receptors is essential for transmission of the mitogenic signal into the cell 6!.
PDGF and its receptors participate in various physiological processes such as embryonal development and wound healing. An abnormally high activity of PDGF is believed to play a central role in the etiology of certain adverse pathophysiological situations, such as atherosclerosis and restenosis 7,8!, as well as in other non-malignant diseases such as pulmonary fibrosis 9!, glomerular nephritis 10!, and rheumatoid arthritis 11!. Moreover, the PDGF .beta.-chain was acquired as the sis oncogene by the acutely transforming simmian sarcoma virus 12, 13!. The expression of a PDGF-like growth factor in cells infected with simian sarcoma virus or transfected with the sis oncogene leads to their transformation due to the persistent (lutocrine stimulation of the resident PDGF receptors.
Furthermore, certain human tumors possess PDGF receptors and express the genes for PDGF which suggests that autocrine growth stimulation via PDGF receptors contributes to the malignant phenotype of these tumors 2,14!.
The fact that PDGF is likely to be involved in the development of certain disorders has prompted the search for agents to block the action of PDGF. The approaches for interference with PDGF-induced signalling include peptides competing with PDGF for receptor binding 15!, dominant negative mutants of PDGF 16, 17! or of PDGF receptor 18!, and low molecular weight blockers of the receptor tyrosine kinase activity known as tyrphostins 19!.
Certain tyrphostins which block PDGF-dependent proliferation of rabbit vascular smooth muscle cells 20! and of human bone marrow fibroblasts 21! have already been reported.
A novel class of tyrosine kinase blockers represented by the tyrphostins AG1295 and AG1296 was described by Kovalenko et al. 22!. These compounds inhibit selectively the platelet-derived growth factor (PDGF) receptor kinase and the PDGF dependent DNA synthesis in Swiss 3T3 cells and in porcine aorta endothelial cells (EC) with 50% inhibitory concentrations below 5 and 1 .mu.M, respectively. These PDGF receptor blockers have no effect on epidermal growth factor receptor autophosphorylation, weak effects on DNA synthesis stimulated by insulin, by epidermal growth factor, or by a combination of both and over an order of magnitude weaker blocking effect on fibroblast growth factor-dependent DNA synthesis.
AG1296 potently inhibits signalling of human PDGF .alpha.- and .beta.-receptors as well as of the related stem cell factor receptor (c-Kit) but has no effect on autophosphorylation of the vascular endothelial growth factor receptor KDR or on DNA synthesis induced by vascular endothelial growth factor in porcine aortic endothelial cells. Treatment by AG1296 reverses the transformed phenotype of sis-transfected NIH 3T3 cells but has no effect on src-transformed NIH 3T3 cells or on the activity of the kinase p60c-src(F527) immunoprecipitated from these cells 22!.
The present invention describe novel and potent tyrphostin compounds which possess an quinoxaline moiety, which show high selectivity towards the PDGF receptor kinase. These compounds are new leads for drugs which could potentially combat malignant as well as non-malignant proliferative disorders in which PDGF plays a prominent role.